The commonly occurring E23K and I337V Kir6.2 polymorphisms in the ATP-sensitive potassium (K ATP ) channel are more frequent in Caucasian type 2 diabetic populations. However, the underlying cellular mechanisms contributing to the pathogenesis of type 2 diabetes remain uncharacterized. Chronic elevation of plasma free fatty acids observed in obese and type 2 diabetic subjects leads to cytosolic accumulation of long-chain acyl CoAs (LC-CoAs) in pancreatic ␤-cells. We postulated that the documented stimulatory effects of LC-CoAs on K ATP channels might be enhanced in polymorphic K ATP channels. Patch-clamp experiments were performed on inside-out patches containing recombinant K ATP channels (Kir6.2/SUR1) to record macroscopic currents. K ATP channels containing Kir6.2 (E23K/I337V) showed significantly increased activity in response to physiological palmitoyl-CoA concentrations (100 -1,000 nmol/l) compared with wild-type K ATP channels. At physiological intracellular ATP concentrations (mmol/l), E23K/I337V polymorphic K ATP channels demonstrated significantly enhanced activity in response to palmitoyl-CoA. The observed increase in K ATP channel activity may result in multiple defects in glucose homeostasis, including impaired insulin and glucagon-like peptide-1 secretion and increased glucagon release. In summary, these results suggest that the E23K/I337V polymorphism may have a diabetogenic effect via increased K ATP channel activity in response to endogenous levels of LC-CoAs in tissues involved in the maintenance of glucose homeostasis. Diabetes 52: 2630 -2635, 2003 T ype 2 diabetes is a multifactorial disease with both genetic and environmental components contributing to its development. Despite the investigation of polymorphic variations in genes encoding for key components in pathways controlling insulin secretion, their precise roles in the etiology of type 2 diabetes are not well understood.Glucose homeostasis is maintained through the coordinated release of several hormones, including insulin, glucagon, and glucagon-like peptide-1 (GLP-1). A key component regulating the release of these hormones is the ATP-sensitive potassium (K ATP ) channel (1-3). Hormone secretion in the pancreatic ␤-and ␣-cell and in the intestinal L-cell is controlled through metabolic regulation of electrical activity, a process critically linked to glucose and fatty acid metabolism, which in turn regulates the activity of K ATP channels that control membrane potential (1-4).The K ATP channel is a hetero-octameric protein complex comprised of the pore-forming inward-rectifier Kir6.2 subunit coupled to the high-affinity sulfonylurea receptor SUR1 subunit (5,6) in a stoichiometry of (Kir6.2) 4 /(SUR1) 4 . Mutations that reduce K ATP channel activity can lead to the increased ␤-cell excitability and excessive insulin secretion that underlies the congenital disorder of persistent hyperinsulinemic hypoglycemia of infancy (7). In addition, transgenic animal models demonstrate that targeted overactivity of K ATP channels severely impair...

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